Process for the preparation of beta-santalol and derivatives thereof

ABSTRACT

The present invention relates to a dienol compound of formula 
     
       
         
         
             
             
         
       
     
     in the form of any one of its stereoisomers or mixture thereof, wherein R represents a methyl or ethyl group; R 1  represents a hydrogen atom or a methyl or ethyl group; R 4  represents a C 1 -C 3  alkyl, alkenyl or acyl group or a C 3 -C 8  silyl group.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/936,325filed Oct. 4, 2010, now U.S. patent ______, which is the 371 filing ofInternational Patent Application PCT/IB2009/052048, filed May 18, 2009.

TECHNICAL FIELD

The present invention relates to the field of organic synthesis and morespecifically it concerns a process for the preparation of a compound offormula

wherein R represents a Me or Et group, and said compound is in the formof any one of its stereoisomers or mixture thereof The inventionconcerns also the compound (I) as well as its precursors and the processto manufacturing compound (I). Furthermore, it concerns also the use ofcompound (I) for the synthesis of β-santalol or of derivatives thereof.

PRIOR ART

The compounds of formula (I) are novel compounds, and are usefulstarting materials for the preparation of β-santalol, and derivativesthereof, in a short and effective manner.

The β-santalol, and derivatives thereof, are well known perfumingingredients, some of which of particular relevance. Therefore, there isalways a need for alternative synthesis to produce them.

To the best of our knowledge, all known syntheses are very long orrequire expensive starting materials or reagents or even steps which aretoo expensive for an industrial process (e.g. see Brunke at al., inRivista Italiana EPPOS, 1997, 49). In particular one may cite thefollowing references, which are representative of the best examples ofprocesses for the preparation of β-santalol:

-   -   EP 10213: however said process, besides the fact that it is very        long, requires many chlorinated intermediates (not optimal for a        use in perfumery) and provides a very low yield (about 13%) for        the preparation of the unsaturated aldehyde (II) of the present        invention (see below);    -   A. Krotz et all, in Tet. Asym, 1990, 1, 537: relatively short        synthesis, however it requires two Wittig reactions, or the        equivalent, and expensive reagents.

The aim of the present invention is to provide a more industrial processfor the preparation of β-santalol, and derivatives thereof. Indeed thepresent invention shortens the overall process of preparation of thetargeted compounds by allowing the one-step creation of a suitablyfunctionalised side-chain moiety (with the correct configuration)together with the concomitant formation of the methylene function(without the mandatory need of a Wittig olefination).

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula

in the form of any one of its stereoisomers or mixture thereof, andwherein R represents a Me or Et group, and R^(a) represents a hydrogenatom or a Si(R^(b))₃ or (R^(c))₂COH group, R^(b) representing C₁₋₅ groupor a phenyl group and R^(c) representing a C₁₋₅ group or a phenyl group.

Indeed, we have now found that β-santalol (an important perfumingingredient), and derivatives thereof, can be advantageously preparedstarting from an enynol of formula (I-a) wherein R^(a) is a hydrogenatom, i.e. a compound of formula

in the form of any one of its stereoisomers or mixture thereof, andwherein R represents a Me or Et group.

In particular, a compound (I) or (I-a) wherein R is Me is the preferredembodiment, since it is a direct precursor of β-santalol.

Compound (I) can be advantageously prepared from the compounds (I-a)wherein R^(a) is not a hydrogen atom. Consequently, a second object ofthe present invention concerns a process for the preparation of acompound (I), as defined above, comprising the following steps:

-   a) reacting 2-R-3-methylene-bicyclo[2.2.1]heptane, wherein R has the    same meaning as for compound (I), with a compound of formula    R^(a)—C≡CCHO, wherein R^(a) represents a Si(R^(b))₃ or (R^(c))₂COH    group, R^(b) and R^(c) representing, independently from each other,    C₁₋₅ group or a phenyl group,-    in the presence of a Al, B or Sn derivative Lewis acid as catalyst    (“ene” reaction),-    to obtain a compound of formula (I-a) wherein R^(a) represents a    Si(R^(b))₃ or (R^(c))₂COH group, R^(b) and R^(c) representing,    independently from each other, C₁₋₅ group or a phenyl group; and-   b) treating the obtained compound (I-a) with a suitable base or a    fluorine salt to obtain compound (I).

According to a particular embodiment, the starting material of the aboveprocess is 2endo-methyl-3-methylene-bicyclo[2.2.1]heptane, in anoptically active or racemic form.

The catalysts necessary for an “ene reaction” are well known by a personskilled in the art, however one may cite, as non limiting examples, thefollowing compounds: Me₂AlCl, EtAlCl₂, SnCl₄ or BF₃.

The bases of fluorine salt necessary for step b) are well known by aperson skilled in the art, however one may cite, as non limitingexamples, the following compounds: KOH, borax (Na₂B₄O₇) or KF.

The compound 2-R-3-methylene-bicyclo[2.2.1]heptane, racemic or in anoptically active form and wherein R has the same meaning provided above,can be obtained according to the methods described in the prior art, ormore conveniently according to a new process, which is also an object ofthe invention, comprising the following steps:

-   a′) reacting cyclopentadiene with a trans aldehyde RHC═CHCHO,    wherein R has the same meaning as above, under Diels Alder    conditions, in the presence of an optically active salt obtained by:-    reacting together an acid H(Anion) and-    a racemic or optically active    2-R^(d)-3-R^(e)-5-R^(f)-4-imidazolidinone derivative or a racemic or    optically active prolinol derivative of formula    (C₄H₈N)-2-CAr₂OSiR^(b) ₃;-    wherein Anions stand for an anion selected in the group consisting    of Cl⁻, ClO₄ ⁻, a R^(g)SO₃ ⁻ or R^(g)CO₂ ⁻, wherein R^(g) is a C₁-C₇    hydrocarbon group or an C₁-C₈ fluoroalkyl or fluoroaryl group, ClSO₃    ⁻, FSO₃ ⁻, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsCl₆ ⁻, SbF₆ ⁻, AsF₆ ⁻ or    B(R^(h))₄ ⁻, wherein R^(h) is a phenyl group optionally substituted    by one to five groups such as halide atoms or methyl or CF₃ groups;-    R^(b) is defined as for compound (I-a); Ar represents a phenyl    group optionally substituted by one, two or three Me, Et CF₃, OMe or    OEt;-    R^(d) represents t-Bu, a phenyl group, a benzyl group or a    5-Me-furyl group;-    R^(e) represents a hydrogen atom, a C₁-C₃ alkyl group or a benzyl    group; and-    R^(f) represents t-Bu, a phenyl group, a benzyl group;-    (to obtain 3-R-bicyclo[2.2.1]hept-5-ene-2exo-carbaldehyde);-   b′) reducing the Diels Alder adduct obtained in step a′) into a    saturated alcohol, and optionally converting said alcohol into an    ester, carbonate or a sulfonate;-   c′) converting said alcohol, ester, carbonate or sulphonate, into    the desired product.

Step a′) is a known reaction and a person skilled in the art is able toapply its standard knowledge to perform them (e.g. see MacMillan et al.in WO 03/002491 or in J. Am. Chem. Soc. 2005, 127, 11616 or see Hayashiet al. in Angew. Chem. Int. ed. 2008, 47, 6634 or in Org. Lett., 2007,9, 2859). Examples of how performing said process is provided in theExample part of the description.

Steps b′) and c′) are well known reactions and a person skilled in theart is able to apply its standard knowledge to perform them. Examples ofhow performing said process is provided in the Example part of thedescription.

For the sake of clarity, by “ester, carbonate or sulfonate” it is meantthe usual meaning in the art, i.e. that the oxygen atom of saidsaturated alcohol is bonded to an acyl, alkoxycarbonyl or sulfonategroup (e.g. a C₁₋₇ group).

Preferably R is a methyl group, and the aldehyde RHC=CHCHO iscrotonaldehyde (i.e. the product obtained by said process, i.e. of stepsa′) and b′) and c′), is 2-Me-3-methylene-bicyclo[2.2.1]heptane).

This process is particularly useful for the preparation of2endo-R-3-methylene-bicyclo[2.2.1]heptane, in an optically active orracemic form, and subsequently a compound of formula (I-a′).

As mentioned above, enynol (I) has been found to be a useful precursorof β-santalol, and derivatives thereof. Indeed enynol (I) can be usedfor the preparation of an aldehyde (II), as defined below, which isknown to be an important intermediate in the preparation of β-santaloland derivatives thereof.

Consequently, the present invention also relates to a process for thepreparation of a compound of formula

-   -   in the form of any one of its stereoisomers or mixture thereof,        and wherein R represents a Me or Et group;        by reacting (cyclisation-fragmentation step) an enynol of        formula

-   -   as defined above;        with a M(L)_(n)Z salt, wherein M represents Zn(II), Cu(I) or        Ag(I), n represents an integer from 0 to 4, L represents a C₁-C₄        nitrile, C₆H₅CN, or di-nitrile, or a C₅-C₈ pyridine derivative,        and Z a weakly or non coordinating anion.

According to a particular embodiment, said M(L)_(n)Z salt is Cu(L)₄Z,wherein L is C₁-C₄ nitrile, or a AgZ salt.

According to a particular embodiment Z is a R⁴SO₃ ⁻, wherein R⁴ is achlorine or fluorine atom or an C₁-C₈ alkyl, fluoroalkyl or fluoroarylgroup, B₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, SbF₆ ⁻, or BR⁵ ₄ ⁻, wherein R⁵ is a phenylgroup optionally substituted by one to five groups such as halide atomsor methyl or CF₃ groups. When M is Ag(I) then Z may also represent anitrate or a perchlorate.

According to a preferred embodiment of the invention, Z is BF₄ ⁻, PF₆ ⁻,SbCl₆ ⁻, C₆F₅SO₃ ⁻, BPh₄ ⁻, CF₃SO₃ ⁻ or yet B[3,5-(CF₃)₂C₆H₄]₄−, morepreferably BF₄−.

Optionally, to said process of the invention, it can be also added, asadditive, an alkaline salt of the anion Z. In particular it can be addeda salt of formula KZ or CsZ.

The transformation of (I) into (II), in any of its embodiments, ispreferably carried out in the presence of solvent. Non-limiting examplesof such a solvent are esters, aromatic hydrocarbons, chlorinatedsolvents and mixtures thereof. More preferably, the solvent is tolueneor 1,2-dichloroethane and mixtures thereof.

The temperature, at which the transformation of (I) into (II) accordingto the invention can be carried out, in any of its embodiments, iscomprised between 0° C. and 150° C., preferably between 40° C. and 70°C. Of course a person skilled in the art is also able to select thepreferred temperature as a function of the melting and boiling point ofthe starting and final products and/or an eventual solvent.

The salt M(L)_(n)Z can be added to the reaction medium in a large rangeof concentrations. As non-limiting examples, one can cite saltconcentrations ranging from 0.01 to 0.50 molar equivalents, relative tothe molar amount of the starting enynol (I). Preferably, the saltconcentration will be comprised between 0.01 and 0.10 molar equivalents.It goes without saying that the optimum concentration of the M(L)_(n)Zwill depend on the nature of the latter and on the desired reactiontime.

The additive can be added to the reaction medium in a large range ofconcentrations. As non-limiting examples, one can cite additiveconcentrations ranging from 10 to 250%, relative to the weight of thesalt. Preferably, the additive concentration will be comprised between10 and 120%, relative to the weight of the salt.

According to any embodiment of the invention, and independently of thespecific aspects, the compounds (I-a), (I) or (II) can be in the form ofany one of its stereoisomers or mixture thereof. By the termstereoisomer it is intended any diastereomer, enantiomer, racemate orcarbon-carbon isomer of configuration E or Z.

According to a particular embodiment of the invention, compound (I-a) isin the form of a mixture of stereoisomers comprising more than 50% (w/w)of the (1R,4S) stereoisomer, i.e. a compound having the absoluteconfiguration as shown in formula (I-a′)

and in a further embodiment said compound (I) consists essentially inthe compound (I-a′).

According to a particular embodiment of the invention, compound (I) isin the form of a mixture of stereoisomers comprising more than 50% (w/w)of the (1R,4S) stereoisomer, i.e. a compound having the absoluteconfiguration as shown in formula (I′)

and in a further embodiment said compound (I) consists essentially inthe compound (I′).

As typical examples of compounds (I) one may cite1-[-3-methylbicyclo[2.2.1]hept-2-en-2-yl]-3-butyn-2-ol or itsstereoisomer1-[(1R,4S)-3-methylbicyclo[2.2.1]hept-2-en-2-yl]-3-butyn-2-ol.

According to a particular embodiment of the invention, compound (II) isin the form of a mixture of isomers comprising more than 50% (w/w) ofthe 2-endo-R configuration. Furthermore, said compound (II) can be inthe form of a mixture of stereoisomers comprising more than 50% (w/w) ofthe (1S,2S,4R) stereoisomer, i.e. a compound having the absoluteconfiguration as shown in formula (II′)

and in a further embodiment said compound (II) consists essentially inthe compound (II′).

As typical examples of compounds (II) one may cite3-[2-methyl-3-methylenebicyclo[2.2.1]hept-2-yl]-acrylaldehyde or itsstereoisomer3-[(1S,2S,4R)-2-methyl-3-methylenebicyclo[2.2.1]hept-2-yl]-acrylaldehyde.

Since compound (I) is a useful starting material for the preparation ofβ-santalol or a derivative thereof, the present invention concerns alsothe use of a compound (I), as intermediate, in the synthesis of acompound of formula (III) as defined herein below. In other words, theinvention concerns also a process for obtaining a compound of formula(β-santalol or derivatives)

-   -   wherein R represents a Me or Et group;    -   R¹ represents a hydrogen atom or a Me or Et group;    -   X represents a CH₂OR², CHO or a CH(OR³)₂ group, R² representing        a hydrogen atom, a C₁-C₃ alkyl, alkenyl or acyl group, R³        representing, when taken separately, a C₁-C₃ alkyl, alkenyl or        acyl group or, when taken together, a C₂-C₅ alkanediyl group;        and    -   the dotted lines represents a single or double bond,    -   said compound being in the form of any one of its stereoisomers        or mixture thereof;        said process comprising the following steps:

-   1) transforming an enynol of formula (I), as defined above, into an    aldehyde of formula (II), as defined above, by a process as    described above; and

-   2) transforming the aldehyde of formula (II), into a compound of    formula (III), as defined above.

According to a particular embodiment of the invention, and independentlyof the specific aspects, R represents a methyl group.

According to a further embodiment of the invention, and independently ofthe specific aspects, R¹ represents a methyl or ethyl group.

According to a further embodiment of the invention, and independently ofthe specific aspects, R² represents a hydrogen atom or a C₁-C₃ acylgroup.

According to a further embodiment of the invention, and independently ofthe specific aspects, R³ represents, when taken separately, a methyl orethyl group or, when taken together, a C₂-C₄ alkanediyl group.

According to a particular embodiment of the invention, and independentlyof the specific aspects, the compounds (III) can be in the form of anyone of its stereoisomers or mixture thereof. By the term stereoisomer itis intended any diastereomer, enantiomer, racemate or carbon-carbonisomer of configuration E or Z.

According to a particular embodiment of the invention, compound (III) isin the form of a mixture of isomers comprising more than 50% (w/w) ofthe 2-endo-R configuration. Furthermore, said compound (III) can be inthe form of a mixture of stereoisomers comprising more than 50% (w/w) ofthe (1S,2S,4R), or even (2Z,1S,2S,4R), stereoisomer, i.e. a compoundhaving the absolute configuration as shown in formula (III′)

and in a further embodiment said compound (III) consists essentially inthe compound (III′).

As typical examples of compounds (III) one may cite the following:β-santalol, (−)-β-santalol (i.e(2Z)-2-methyl-5-[1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]hept-2-yl]-2-penten-1-ol),β-santalal, β-santalyl benzoate, β-santalyl butyrate, β-santalylformate, β-santalyl proprionate.

The first step of the process is as defined above.

The transformation of the aldehyde (II) into the compound (III) can beperformed in many different manners, which are well known by a personskilled in the art. Practical examples are provided in Examples hereinbelow.

However, as non-limiting example, one of the most direct manners totransform the aldehyde (II) into the compound (III) comprises thefollowing reactions:

-   i) coupling of aldehyde (II) with Ph₃P═CHR¹ and then reacting the    glide with CH₂O and BuLi (Wittig addition followed by a    hydroxyalkylation) to obtain an alcohol or a carboxylate derivative.-   ii) transformation of the alcohol into the suitable ester, aldehyde    or acetal.

An optional step of partial or total hydrogenation of the C=C bonds canbe perfomed at any moment, i.e. before step i), or just after step i) orii).

The Wittig-hydroxyalkylation addition can be performed according to themethod reported by R. Snowden et al. in Helvetica Chemica Acta, 1981,64, 25.

The Wittig addition allows obtaining directly compound (III) where Xrepresents CH₂OR², wherein R² is a hydrogen atom or some acyl groups. Ifa compound (III) with a different meaning of R² is desired, then saidcompound can be obtained by converting the alcohol (III) (X being CH₂OH)with any standard method as well known by a person skilled in the art.For example, an aldehyde of formula (III) can be obtained by oxidationof the alcohol (III), or an ester (III) can be obtained byesterification of said alcohol (III), etc.

Alternatively, the aldehyde (II) can be converted into the compound(III′), see below, by performing the following reactions:

-   a) reducing (hydrogenation) the aldehyde (II) into and aldehyde of    formula (IV)

-    in the form of any one of its stereoisomers or mixture thereof, and    wherein R has the same meaning as in formula (II);-   b) coupling said aldehyde (IV) with an aldehyde R¹CH₂CHO (Aldol    addition) to obtain an aldehyde (V)

-    in the form of any one of its stereoisomers or mixture thereof, and    wherein R and R¹ have the same meaning as in formula (II);-   c) converting said compound (V) into the corresponding dienol    derivative (VI)

-    in the form of any one of its stereoisomers or mixture thereof, and    wherein R and R¹ have the same meaning as in formula (II), R⁴    represents a C₁-C₃ alkyl, alkenyl or acyl group or a C₃-C₈ silyl    group;-   d) reducing the enolate (VI) into a compound (VII)

-    in the form of any one of its stereoisomers or mixture thereof, and    wherein R, R¹ and R⁴ have the same meaning as in formula (VI);-   e) optionally, transforming said compound (VII) into a compound    (III″)

-    in the form of any one of its stereoisomers or mixture thereof, and    wherein the dotted lines, R, R¹ and X have the same meaning as in    formula (III).

Step e) is described as optional only because many of the compounds(VII) are already included in formula (III), and therefore, depending onthe desired compound (III) the last step is not necessary.

According to a particular embodiment of the invention, said compounds(IV) to (VII) possess a configuration corresponding to the one describedabove for compounds (II′) or (III′).

Steps a) to e) can be performed according to standard methods well knownby a person skilled in the art.

For instance, one may cite the following method for each step:

step a) or b) according to EP 10213;step c) according to Simmons et al. in Helv. Chim. Acta, 1988, 71, 1000,or WO 2005/037243; andstep d) according to Shibasaki et al., in J. Org. Chem., 1988, 53, 1227(where is reported the [1,4] hydrogenation of a dienol acetatederivative) or according to WO 08/120175.

An example of such procedure is provided in the Examples herein below.

EXAMPLES

The invention, in all its embodiments, will now be described in furtherdetail by way of the following examples, wherein the abbreviations havethe usual meaning in the art, the temperatures are indicated in degreescentigrade (° C.); the NMR spectral data were recorded in CDCl₃ with a400 MHz or 125 MHz machine for ¹H or ¹³C respectively, the chemicalshifts δ are indicated in ppm with respect to TMS as standard, thecoupling constants J are expressed in Hz.

Example 1

Preparation of a compound (I)—Method A:a) Preparation of 3-exo-Methyl-bicyclo[2.2.1]heptan-2-one

A solution of butyllithium in hexanes (1.58 M, 260.0 ml, 410.8 mmol) wasadded over a 40 minutes period to diisopropylamine (59.0 ml, 419.8 mmol)in solution in THF (100 ml) at −78° C. under nitrogen. The mixture wasfurther stirred at −78° C. for 30 minutes, then (±)-norcamphor (40.118g, 364.2 mmol) in THF (100 ml) was added dropwise at −78° C. and stirredfor further 30 minutes at −78° C., before adding iodomethane (34.0 ml,545.9 mmol). Once the addition was finished, the mixture was stirred forfurther 30 minutes at −78° C. and was allowed to reach room temperature.The mixture was hydrolyzed with a saturated aqueous solution of NH₄Cl.The aqueous layer was extracted twice with pentane, and the combinedorganic layers were washed with a saturated aqueous solution of NH₄Cl, asaturated aqueous solution of NaHCO₃ and brine. The organic layer wasdried over Na₂SO₄, filtered off, and solvents were removed under slightvacuum to give a crude which was further purified by bulb to bulbdistillation under reduced pressure to give the title compound (46.05 g)in quantitative yield.

¹H NMR: 2.54 (br s, 1H), 2.32 (br s, 1H), 1.89-1.77 (m, 4H), 1.53-1.42(m, 3H), 1.05 (d, J=7.6, 3H).

¹³C NMR: 220.9, 49.5, 48.3, 41.5, 34.4, 28.0, 23.8, 14.1.

b) Preparation of (3-exo-Methyl-bicyclo[2.2.1]hept-2-ylidene)-aceticacid

NaH (55%, 19.76 g, 451.45 mmol) and THF (400 ml) were placed in areactor under nitrogen. Triethylphosphonoacetate (94.0 ml, 469.60 ml)was added to the suspension over a 25 minutes period at roomtemperature. The mixture was then heated at 50° C. for 45 minutes,3-exo-methyl-bicyclo[2.2.1]heptan-2-one (46.054 g, 361.59 mmol) in THF(100 ml) was added to the ylide at 50° C. over a 25 minutes period. Oncethe addition finished, the mixture was refluxed for 2 hours. The mixturewas then cooled down to room temperature and hydrolyzed with aqueous HCl5% and ice. The mixture was extracted twice with Et₂O. The combinedorganic layers were washed with water, saturated aqueous NaHCO₃ andbrine. The solution was dried over Na₂SO₄, filtered off and solventswere removed under vacuum to give a crude which was bulb to bulbdistilled under reduced pressure to furnish a product containing 85.5%of (3-methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acid ethyl ester(76.36 g).

KOH pellets (36.31 g, 350.0 mmol) were dissolved in H₂O (220 ml) at roomtemperature and (3-methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acidethyl ester (76.361 g, 361.59 mmol) in absolute ethanol (500 ml) wasadded and the mixture was heated to reflux for 3.5 hours. The solutionwas allowed to reach room temperature and was extracted twice withpentane. The combined organic layers were washed with aqueous NaOH 5%,H₂O, and basic layers were acidified with concentrated HCl until pH=1.The acidic aqueous fraction was extracted twice with pentane, and thecombined organic were washed with aqueous HCl 5%, H₂O, brine, dried overNa₂SO₄ and filtered off. Solvents were removed under vacuum to give acrude which was purified by bulb to bulb distillation under reducedpressure to afford the desired compound (46.575 g) in 75% yield over twosteps.

¹H NMR (E-isomer): 12.10 (br s, 1H), 5.72 (s, 1H), 2.80 (d, J=7.0, 2H),2.10 (br s, 1H), 1.79-1.57 (m, 3H), 1.30-1.18 (m, 3H), 1.12 (d, J=7.0,3H).

¹H NMR (Z-isomer): 12.10 (br s, 1H), 5.53 (s, 1H), 3.97 (br s, 1H), 2.17(d, J=7.2, 1H), 2.04 (br s, 1H), 1.79-1.57 (m, 3H), 1.30-1.18 (m, 3H),1.03 (d, J=7.2, 3H).

¹³C NMR (E-isomer): 179.2, 172.4, 108.9, 47.7, 44.2, 43.8, 35.0, 29.8,27.5, 17.2.

¹³C NMR (Z-isomer): 178.4, 172.7, 108.9, 45.5, 42.9, 41.9, 35.8, 28.1,27.8, 19.1.

c) Preparation of 3(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetic acid

A solution of butyllithium in hexanes (1.40 M, 616.0 ml, 862.4 mmol) wasadded over a 60 minutes period to diisopropylamine (125.0 ml, 888.9mmol) in THF (200 ml) at −78° C. under nitrogen. The mixture was furtherstirred at −78° C. for 30 minutes, then(3-methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acid (46.57 g, 280.2mmol) in THF (200 ml) was added dropwise at −78° C. Once the additionfinished the mixture was stirred for further 30 minutes at −78° C. andwas allowed to reach room temperature. The orange mixture was hydrolyzedwith aqueous HCl 5%. The aqueous layer was extracted twice with Et₂O,and the combined organic layers were washed twice with H₂O. The organiclayer was extracted twice with aqueous NaOH 5% until pH=11, and thebasic layers were acidified with concentrated HCl until pH=1. Theaqueous fraction was extracted twice with Et₂O and the combined organicfractions were washed with H₂O, brine, dried over Na₂SO₄ and filteredoff. The solvents were removed under vacuum to give a crude which wasfurther purified by bulb to bulb distillation under reduced pressure toafford the desired compound (42.24 g, 95% purity) in 86% yield.

¹H NMR: 11.09 (br s, 1H), 3.12 (d of AB syst., J=15.2, 1H), 3.00 (d ofAB syst., J=15.2, 1H), 2.80 (s, 1H), 2.62 (s, 1H), 1.66 (s, 3H),1.63-1.61 (m, 2H), 1.40 (dt, J¹=8.1, J²=2.0, 1H), 1.10-1.00 (m, 3H).

¹³C NMR: 178.6, 141.0, 131.5, 47.7, 46.8, 45.9, 32.6, 26.2, 25.4, 11.9.

d) Preparation of (±)-2-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-ethanol

3(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetic acid (42.240 g, 254.2mmol) in dry Et₂O (500 ml) was added over a 60 minutes period to lithiumaluminum hydride (14.99 g, 381.2 mmol) in Et₂O (250 ml) under nitrogenat room temperature. Once the addition finished, the mixture was heatedto reflux for 1.5 hours and was then cooled down to 0° C. The mixturewas slowly hydrolyzed with 14.0 ml of H₂O and 14.0 ml of aqueous NaOH5%. Celite and Na₂SO₄ were added to the crude mixture. The suspensionwas filtered off through celite and solvent was removed under vacuum togive a crude which was further purified by bulb to bulb distillationunder reduced pressure to afford the desired compound (42.24 g, 89%purity) in 76% yield.

¹H NMR: 3.66 (t, J=6.0, 2H), 2.70 (s, 1H), 2.61 (s, 1H), 2.37 (td,J¹=13.8, J²=6.6, 1H), 2.20 (td, J¹=13.8, J²=6.6, 1H), 1.65 (s, 3H),1.64-1.62 (m, 2H), 1.44 (br s, 1H), 1.30 (dt, J¹=8.0, J²=2.0, 1H),1.06-1.01 (m, 3H).

¹³C NMR: 140.4, 135.8, 61.1, 47.7, 46.9, 45.0, 30.3, 26.5, 25.4, 11.9.

e) Preparation of(±)-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde

2-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-ethanol (16.37 g, 107.53 mmol)was dissolved in dichloromethane (150 ml) and Dess-Martin periodinane insolution in dichloromethane (15%, 536.2 g, 189.7 mmol) was added at roomtemperature over a 110 minutes period under nitrogen. The mixture wasfurther stirred at room temperature for 30 minutes and was hydrolyzedwith aqueous NaOH 5% in an ice-bath, and extracted 3 times with Et₂O.The combined organic layers were washed with H₂O, brine, dried overNa₂SO₄, and filtered off. Solvents were removed under reduced pressureto give a crude which was further purified by bulb to bulb distillationunder reduced pressure to afford the desired compound (13.468 g, 88%purity) in 83% yield.

¹H NMR: 9.57 (t, J=2.6, 1H), 3.15 (dd, J¹=16, 1H), 3.05 (d, J=16, 1H),2.68 (d, J=14.3, 2H), 1.67 (s, 3H), 1.65-1.63 (m, 2H), 1.42-1.39 (m,1H), 1.09-1.01 (m, 3H).

¹³C NMR: 199.7, 142.5, 130.1, 47.8, 46.9, 46.0, 42.8, 26.2, 25.3, 12.1.

f) Preparation of(±)-1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol

Ethynylmagnesium bromide in THF (0.5 M, 210.0 ml, 105.0 mmol) was placedin a reactor under a nitrogen atmosphere at room temperature and(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde (12.15 g, 80.9mmol) in THF (200 ml) was introduced over a 90 minutes period and themixture turned orange. The mixture was further stirred at roomtemperature for 30 minutes and was hydrolyzed with aqueous HCl 5% atroom temperature. The mixture was extracted twice with Et₂O and thecombined organic layers were washed twice with a saturated aqueoussolution of NaHCO₃, H₂O, and brine and dried over Na₂SO₄. Solvents wereremoved under vacuum to give a crude which was purified by flashchromatography with cyclohexane/AcOEt (95/5) as eluent to afford thetitle compound (11.32 g) in 79% yield.

¹H NMR (isomer A): 4.44 (br s, 1H), 2.76 (s, 1H), 2.63 (s, 1H), 2.52(dd, J¹=13.8, J²=8.1, 1H), 2.40 (d, J=2.0, 1H), 2.44 (dd, J¹=13.8,J²=5.9, 1H), 1.98 (br s, 1H), 1.67 (s, 3H), 1.64-1.62 (m, 2H), 1.34-1.32(m, 1H), 1.11-1.00 (m, 3H).

¹H NMR (isomer B): 4.46 (br s, 1H), 2.86 (s, 1H), 2.62 (s, 1H), 2.53 (ddof AB syst., J¹=13.8, J²=6.3, 1H), 2.43 (d, J=2.1, 1H), 2.39 (dd of ABsyst., J¹=13.8, J²=5.7, 1H), 2.03 (br s, 1H), 1.67 (s, 3H), 1.64-1.62(m, 2H), 1.39-1.36 (m, 1H), 1.11-1.01 (m, 3H).

¹³C NMR (isomer A): 142.2, 134.4, 84.8, 72.6, 60.9, 47.7, 46.9, 45.2,35.7, 26.4, 25.2, 12.0.

¹³C NMR (isomer B): 141.9, 134.6, 85.1, 72.7, 61.3, 47.8, 46.9, 46.0,35.1, 26.5, 25.3, 12.1.

Preparation of a compound (I)—Method Ba ) Preparation of 3-Methylene-bicyclo[2.2.1]heptan-2-one

Diethylamine (50.0 ml, 455.0 mmol) was added over a 15 min. period toformaldehyde (36% in MeOH/H₂O, 50.0 ml, 1.82 mol) at 0° C. The resultantmixture was treated over a 33 minutes period with acetic acid (50.0 ml,910.0 mmol). Once the addition was finished, the temperature wasincreased to room temperature and the mixture was added over a 22minutes period to (±)-norcamphor (50.0 g, 0.455 mol) in the presence ofa small amount of BHT at 95° C. The mixture was refluxed for 5 hours andcooled down to room temperature. The yellow mixture was hydrolyzed withaqueous HCl 5% and ice (pH=1). The aqueous layer was extracted twicewith Et₂O, and the combined organic layers were washed with H₂O, aqueousNaOH 5% and twice with brine, dried over Na₂SO₄ and filtered off. Et₂Owas distilled under atmospheric pressure to give a crude which wasfurther purified by bulb to bulb distillation under reduced pressure toafford the desired compound (26.800 g) in 48% yield.

¹H NMR: 5.72 (s, 1H), 5.16 (s, 1H), 3.13 (br s, 1H), 2.73 (d, J=2.8,1H), 1.90-1.86 (m, 2H), 1.77-1.73 (m, 1H), 1.64-1.61 (m, 1H), 1.57-1.53(m, 2H).

¹³C NMR: 205.8, 150.1, 111.7, 49.2, 42.5, 36.8, 28.1, 23.6.

b) Preparation of (±)-3-endo-Methyl-bicyclo[2.2.1]heptan-2-one

3-Methylene-bicyclo[2.2.1]heptan-2-one (29.670 g at 64.4%, 0.157 mmol)was hydrogenated (atmospheric pressure) in presence of Pd/C (10% in Pd,1.480 g, 5% w/w) in Et₂O (300 ml) at room temperature for 2 hours. Themixture was filtered through “filter cel” and Et₂O was removed bydistillation to give a crude which was further purified by distillation(20 mbar, 87-88° C.) to afford the title compound (19.82 g) inquantitative yield.

¹H NMR: 2.60 (d, J=4.8, 1H), 2.53 (s, 1H), 2.15-2.08 (m, 1H), 1.86-1.77(m, 1H), 1.72-1.68 (m, 1H), 1.65-1.56 (m, 3H), 1.43-1.36 (m, 1H), 1.02(d, J=7.2, 3H).

¹³C NMR: 220.6, 50.3, 48.3, 40.5, 37.2, 25.4, 21.0, 10.8.

c) Preparation of (±)-2-endo-Methyl-3-methylene-bicyclo[2.2.1]heptane:by a Wittig reaction

Methyltriphenylphosphonium bromide (13.31 g, 36.9 mmol) in THF (40.0 ml)was treated in one portion with t-BuOK (6.910 g, 61.6 mmol) at roomtemperature under nitrogen. The resultant yellow mixture was stirred atroom temperature and 3-methyl-bicyclo[2.2.1]heptan-2-one (4.0 g, 30.8mmol) in THF (16.0 ml) was added over a 8 minutes period and was stirredat room temperature for 15 minutes. The mixture was poured over asaturated aqueous solution of ammonium chloride and was extracted twicewith pentane. The combined organic layers were washed with water andbrine, dried over Na₂SO₄ and filtered off. Solvents were removed bydistillation at atmospheric pressure and the crude mixture was furtherpurified by bulb to bulb distillation to afford the desired compound(2.845 g) as colourless oil in 76% yield.

¹H NMR: 4.77 (d, J=2.7, 1H), 4.51 (s, 1H), 2.66 (d, J=3.6, 1H),2.37-2.34 (m, 1H), 2.15 (br s, 1H), 1.67-1.52 (m, 2H), 1.45-1.30 (m,3H), 1.22-1.16 (m, 1H), 1.02 (d, J=7.0, 3H).

¹³C NMR: 161.7, 100.3, 46.5, 42.3, 41.34, 39.5, 30.8, 21.4, 15.1.

d) Preparation of trimethylsilyl-propynal

Trimethylsilylethyne (5.0 ml, 36.10 mmol) in THF (25.0 ml) was dropwiseadded to a solution of EtMgBr in THF (1M, 44.0 ml, 44.0 mmol) at 10-15°C. under nitrogen. Once the addition finished, the mixture was stirredat room temperature for one hour and was added over a 30 min. period toan efficiently stirred mixture of DMF (10.0 ml, 123.0 mmol) in Et₂O(20.0 ml) at −25° C. The white suspension was allowed to reach roomtemperature, stirred for one hour, heated at 30° C. for 15 minutes, andpoured into H₂SO₄ 5% at 0° C. The aqueous layer was extracted threetimes with Et₂O, the combined organic layers were washed with asaturated aqueous solution of NH₄Cl, dried over Na₂SO₄, and the solventswere carefully removed under vacuum to give a crude which was furtherpurified by bulb to bulb distillation (20 mBar, room temperature) toafford the title compound (2.255 g) in 49% yield.

¹H NMR: 9.15 (s, 1H), 0.25 (s, 9H).

¹³C NMR: 176.7, 103.0, 102.3, 0.88.

e) Preparation of1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-4-trimethylsilanyl-but-3-yn-2-olvia ene-reaction

Me₂AlCl (1M in hexanes, 1.1 ml, 1.1 mmol) was dropwise added to asolution of trimethylsilyl-propynal (154.0 mg, 1.22 mmol) and2-endo-methyl-3-methylene-bicyclo[2.2.1]heptane (140.0 mg, 1.15 mmol) indichloromethane (5.0 ml) at −78° C. under nitrogen. The mixture wasstirred at −78° C. for 15 minutes and was hydrolyzed with aqueous HCl5%. The temperature was then slowly allowed to increase to roomtemperature and extracted twice with CH₂Cl₂. The combined organic layerswere washed with water, brine, dried over Na₂SO₄ and filtered off togive a crude which was further purified by flash chromatography withcyclohexane/AcOEt (97/3) as eluent to afford title compound (148.0 mg)in 59% yield.

Ene-reaction could also be performed at −78° C. with BF₃.Et₂O (5 mol %)as catalyst in dichloromethane at −78° C. with complete conversion in 5minutes.

f) Preparation of1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol

Simple treatment of1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-4-trimethylsilanyl-but-3-yn-2-olwith an excess of K₂CO₃ in methanol for 1 hour at room temperatureafforded 1-(3-methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol inquantitative yield.

¹H NMR: 4.42 (dd, J¹=J²=7.0, 1H), 2.75 (s, 1H), 2.60 (s, 1H), 2.52-2.47(m, 1H), 2.42-2.35 (m, 1H), 1.91 (br s, 1H), 1.66 (s, 3H), 1.62-1.60 (m,2H), 1.34-1.32 (m, 1H), 1.11-0.99 (m, 3H), 0.15 (s, 9H). ¹³C NMR: 141.8,134.7, 106.8, 89.3, 61.7, 47.8, 47.1, 45.6, 36.0, 26.6, 25.3, 12.1,10.0.

Example 2 Preparation of a Compound (II)

a) Preparation of3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al withCuBF₄(CH₃CN)₄

CuBF₄(CH₃CN)₄ (0.294 g, 0.93 mmol) was added to a two-rounded bottomflask charged with1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (3.24 g, 18.4mmol) in solution in 1,2-dichloroethane (100 ml) at room temperatureunder nitrogen. The mixture was stirred at 50° C. for 140 minutes. Thecrude mixture was allowed to reach room temperature and was filteredthrough a short pad of silica gel with CH₂Cl₂ as eluent. Solvents wereremoved under vacuum to give a crude which was further purified by bulbto bulb distillation under reduced pressure to afford the title compound(3.12 g) in 96% yield.

¹H NMR: 9.52 (d, J=7.8, 1H), 6.77 (d, J=15.7, 1H), 6.09 (dd, J¹=15.7,J²=7.8, 1H), 5.01 (s,1H), 4.58 (s, 1H), 2.76 (br s, 1H), 2.18 (br s,1H), 1.80-1.69 (m, 2H), 1.58-1.52 (m, 2H), 1.37-1.30 (m, 1H), 1.27-1.24(m, 1H), 1.23 (s, 3H).

¹³C NMR: 194.5, 165.4, 160.4, 130.1, 104.1, 49.7, 46.5, 46.3, 37.1,29.8, 23.0, 22.7.

b) Preparation of3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al withAgBF₄

AgBF₄ (20.0 mg, 0.10 mmol) was added to a two-rounded bottom flaskcharged with 1-(3-methyl bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol(371.0 mg, 2.10 mmol) in solution in 1,2-dichloroethane (10 ml) at roomtemperature under nitrogen. The mixture was stirred at 50° C. for 80minutes in the dark. The crude mixture was allowed to reach roomtemperature and was filtered through a short pad of silica gel withCH₂Cl₂ as eluent. Solvents were removed under vacuum to give a crudewhich was further purified by flash chromatography withcyclohexane/AcOEt (97/3) as eluent to afford the title compound (172.0mg) in 46% yield.

c) Preparation of3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al withAgNO₃ in presence of KNO₃ as additive

AgNO₃ (17.6 mg, 0.10 mmol) and KNO₃ (107.0 mg, 1.06 mmol) was added to atwo-rounded bottom flask charged with 1-(3-methylbicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (181.0 mg, 1.03 mmol) insolution in THF/H₂O (2/1, 10 ml) at room temperature under nitrogen. Themixture was stirred at reflux for 6.5 hours in the dark and AgNO₃ (18.5mg, 0.11 mmol) was added to the mixture before being cooled down to roomtemperature and stirred overnight in the dark. The crude mixture wasdiluted with Et₂O (10 ml) and the aqueous layer was extracted with Et₂O.The combined organic layers were filtered through a short pad of silicagel with CH₂Cl₂ as eluent. Solvents were removed under vacuum to give acrude which was further purified by flash chromatography withcyclohexane/AcOEt (95/5) as eluent to afford the title compound (115.0mg) in 64% yield.

Example 3 Preparation of a Compound (III) and of Derivatives Thereof

a) Preparation of a compound (IV):3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-1-al

Pd/CaCO₃ (5% w/w, 93.0 mg) was placed into a two neck round bottom flaskin methanol (30 ml) and the atmosphere was purged with N₂ before adding3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al (1.886g, 10.70 mmol). The atmosphere was further purged with nitrogen followedwith hydrogen at room temperature. The mixture was stirred at roomtemperature under one atmosphere of hydrogen for 4.5 hours. The mixturewas filtered through “filter cel” to give a crude which was furtherpurified by flash chromatography with pentane/Et₂O (97/3) as eluent toafford the title compound (1.627 g) in 85% yield.

¹H NMR: 9.78 (t, J=1.9, 1H), 4.79 (s, 1H), 4.49 (s, 1H), 2.69 (d, J=3.9,1H), 2.49-2.41 (m, 2H), 2.02 (br s, 1H), 1.75-1.54 (m, 5H), 1.47-1.38(m, 1H), 1.28-1.19 (m, 2H), 1.02 (s, 3H).

¹³C NMR: 202.8, 165.0, 100.6, 46.7, 45.0, 44.1, 40.1, 37.0, 32.6, 29.6,23.6, 22.5.

A) Preparation of β-santalol (via Wittig and hydroxyalkylation reaction)

A solution of butyllithium in hexanes (1.35 M, 11.7 ml, 15.8 mmol) wasadded over a 15 minutes period to a stirred suspension ofethyltriphenylphosphonium iodide (6.61 g, 15.8 mmol) in THF (125 ml) at0° C. The resultant red solution was cooled to −78° C. and3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propanal (2.55 g,14.33 mmol) in solution in THF (16 ml) was added over a 15 minutesperiod. After further 5 minutes at −78° C., a solution of butyllithiumin hexanes (1.35 M, 12.7 mL, 17.2 mmol) was added over a 5 minutesperiod and the mixture was further stirred for 20 minutes at −78° C.before allowing to reach 0° C. in 2 hours. Dry paraformaldehyde (2.60 g,86.0 mmol) was added in one portion to the deep red homogeneous solutionand the mixture was stirred for 30 minutes at 0° C. and was allowed toreach room temperature. After 1 hour at room temperature the mixture waspoured into 5.2 ml of saturated aqueous solution of NH₄Cl and extractedtwice with CH₂Cl₂. The organic layer was washed with water and brine,and dried with Na₂SO₄. The mixture was filtered through a short pad ofsilica gel with dichloromethane as eluent and solvents were removedunder pressure to give a crude. Purification of crude compound wasperformed by flash chromatography on silica gel with cyclohexane/AcOEt90/10) as eluent to give pure β-santalol as pale yellow oil. Furtherbulb to bulb distillation under reduced pressure afforded β-santalol in50% yield (Z:E=95:5).

¹H NMR (CDCl₃, 400 MHz): 5.29 (t, J=7.5, 1H), 4.73 (s, 1H), 4.45 (s,1H), 4.14 (s, 2H), 2.66 (d, J=3.8, 1H), 2.12-1.94 (m, 3H), 1.78 (d,J=1.2, 3H), 1.71-1.60 (m, 3H), 1.44-1.36 (m, 2H), 1.32 (br s, 1H),1.27-1.17 (m,3H), 1.04 (s, 3H).

¹³C NMR (CDCl₃, 125 MHz): 166.2, 133.9, 129.0, 99.7, 61.6, 46.8, 44.7,44.6, 41.5, 37.1, 29.7, 23.7, 23.2, 22.6, 21.2.

B) Preparation of β-santalol (via [1,4] hydrogenation)

i) Preparation of a compound (V):2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-exo-2-yl)-pent-2-enal

3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-1-al (274.0mg, 1.54 mmol) was dissolved in toluene (15.0 ml) at room temperatureunder nitrogen. The mixture was heated to reflux and propionaldehyde(0.4 ml, 1.96 mmol) and aqueous catalytic solution of hexamethyleneimineand benzoic acid (0.12 ml, 0.616 mmol) was separately added in oneportion. Once that addition was finished, the mixture was further heatedat reflux for 6 hours. The mixture was cooled down to room temperatureand extracted twice with brine, the organic layer was dried over MgSO₂,filtered off and concentrated to give a crude which was further purifiedby flash chromatography with cyclohexane/AcOEt (95/5) to afford thetitle compound in 80% yield.

¹H NMR: 9.38 (s, 1H), 6.48 (dt, J¹=7.5, J²=1.2, 1H), 4.78 (s, 1H), 4.49(s, 1H), 2.69 (d, J=3.9, 1H), 2.40-2.29 (m, 2H), 2.12 (d, J=3.1, 1H),1.75 (s, 3H), 1.72-1.64 (m, 3H), 1.59-1.51 (m, 1H), 1.47-1.36 (m, 2H),130-1.21 (m, 2H), 1.09 (s, 3H).

¹³C NMR: 195.2, 165.5, 155.2, 139.1, 100.3, 46.8, 44.8, 44.7, 39.4,37.1, 29.6, 24.9, 23.7, 22.6, 9.1.

ii) Preparation of a compound (IV): Acetic acid2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-1,3-dienylester

To a stirred solution of2-methyl-3-methyl-3-methylene-bicyclo[2.2.1]hept-2-yl)-pent-2-enal(268.0 mg, 1.23 mmol) in toluene (3.0 ml) were added Ac₂O (0.35 ml, 3.70mmol), Et₃N (0.70 ml, 5.02 mmol), and a catalytic amount of DMAP (15.0mg, 0.1 mmol). The resulting mixture was heated to reflux for 22 hours.The mixture was cooled down to room temperature and quenched with brine,extracted twice with Et₂O, dried over MgSO₄, filtered off andconcentrated to give a crude which was further purified by flashchromatography with cyclohexane/AcOEt (98/2) to afford the titlecompound in 82% yield (E:Z=79:21).

¹H NMR: 7.18 (s, 1H), 5.99 (d, J=12.4, 1H), 5.72 (dt, J¹=12.4, J²=6.1,1H), 4.76 (s, 1H), 4.47 (s, 1H), 2.68 (d, 3.4, 1H), 2.17 (s, 3H),2.12-2.01 (m, 2H), 1.81 (d, J=1.0, 3H), 1.73-1.63 (m, 3H), 1.43-1.39 (m,2H), 1.27-1.18 (m, 2H), 1.02 (s, 3H).

¹³C NMR: 167.9, 165.5, 134.4, 130.6, 126.9, 120.7, 100.0, 46.9, 45.3,45.0, 44.5, 37.0, 29.7, 23.6, 23.0, 20.8, 10.4.

iii) Preparation of (2Z)-Acetic acid2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-pent-2-enylester (VII)

Acetic acid2-methyl-3-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-1,3-dienylester (6.80 g, 93% pure; 24.3 mmol 0.18 mmol) was treated with[(Cp*)Ru(COD)]BF₄ (52 mg, 0.122 mmol) and maleic acid (230 mg, 1.95mmol) in dry and degassed acetone (20 ml) at 60° C. under 4 bars of H₂for 24 hours. The product was extracted with pentane/5% NaOH, washedtwice with saturated aqueous NaCl, dried (Na₂SO₄) and bulb-to-bulbdistilled: 6.80 g (81% Z and 5% E by GC; 92%).

¹H NMR: 5.38 (t, J=7.1, 1H), 4.73 (s, 1H), 4.59 (s, 1H), 4.45 (s, 1H),2.66 (br s, 1H), 2.12-2.04 (m, 4H), 2.07 (s, 3H), 1.73 (d, J=1.0, 3H),1.69-1.61 (m, 3H), 1.45-1.37 (m, 2H), 1.27-1.17 (m, 3H), 1.04 (m, 3H).

¹³C NMR: 171.1, 166.1, 131.4, 129.4, 99.7, 63.2, 46.8, 44.7, 44.6, 41.2,37.1, 29.7, 23.7, 23.4, 22.6, 21.5, 21.0.

iv) Preparation of and β-santalol (III)

Simple treatment with an excess of K₂CO₃ in methanol for 1 hour at roomtemperature afforded β-santalol in quantitative yield.

C) Preparation of Compounds (III) with All Dotted Lines Being C═C

i) Preparation of2-Methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-2,4-dienoicacid ethyl ester

NaH (55%, 168.0 mg, 3.85 mmol) and THF (5.0 ml) were placed in a reactorand 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (939.0 mg, 3.94mmol) was added dropwise at room temperature to the suspension over a 10minutes period. The mixture was heated at 50° C. for 45 minutes3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al (566.0mg, 3.21 mmol) in THF (2.0 ml) was added dropwise to the glide at 50° C.Once the addition finished, the mixture was refluxed for 1 hour. Themixture was then cooled down to room temperature and hydrolyzed withaqueous HCl 5%. The reaction was extracted twice with Et₂O. The combinedorganic layers were washed with water, aqueous saturated NaHCO₃ andbrine. The solution was dried over Na₂SO₄, filtered off and solventswere removed under vacuum to give a crude which was further purified bybulb to bulb distillation under reduced pressure to afford the titlecompound (651.0 mg) in 78% yield.

¹H NMR: 7.18 (d, J=11.2, 1H), 6.31 (dd, J¹=15.2, J²=11.2, 1H), 6.05 (d,J=15.2, 1H), 4.98 (s, 1H), 4.56 (s, 1H), 4.20 (q, J=7.1, 2H), 2.73 (d,J=3.2, 1H), 2.09 (d, J=3.1, 1H), 1.92 (d, J=1.2, 3H), 1.73-1.65 (m, 2H),1.61-1.57 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.27 (m, 1H), 1.29 (t, J=7.1,3H), 1.19-1.18 (m, 1H), 1.18 (s, 3H).

¹³C NMR: 168.6, 161.8, 150.2, 138.8, 125.5, 123.0, 103.2, 60.4, 49.6,47.0, 46.4, 37.1, 30.1, 23.5, 23.0, 14.3, 12.7.

ii) Preparation of2-Methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-pent-2.4-dien-1-ol

Dibal-H (1M in toluene, 5.5 ml, 5.5 mmol) was added over a 25 minutesperiod to a stirred solution of2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-2,4-dienoicacid ethyl ester (651.0 mg, 2.50 mmol) in dichloromethane (20.0 ml) at−78° C. under nitrogen.

The resulting mixture was stirred at −78° C. for 70 minutes and wasplaced at 0° C. to be quenched with aqueous HCl 5% and brine. Themixture was extracted twice with CH₂Cl₂, dried over Na₂SO₄, filtered offand concentrated to afford a crude which was further purified by flashchromatography with cyclohexane/AcOEt (9/1) as eluent to afford thetitle compound (453.0 mg) in 83% yield.

¹H NMR: 6.22 (dd, J¹=12.2, J²=8.6, 1H), 6.03 (d, J=8.6, 1H), 5.69 (d,J=12.2, 1H), 4.95 (s, 1H), 4.54 (s, 1H), 4.05 (s, 2H), 2.71 (d, J=2.7,1H), 2.04 (br s, 1H), 1.78 (s, 3H), 1.71-1.62 (m, 3H), 1.58 (br s, 1H),1.42-1.49 (m, 1H), 1.31-1.26 (m, 1H), 1.17-1.15 (m, 1H), 1.16 (s, 3H).

¹³C NMR: 162.4, 142.9, 135.2, 125.7, 122.9, 102.6, 68.8, 49.1, 47.2,46.5, 37.1, 30.2, 23.9, 23.0, 14.3.

Example 4 Preparation of (−)-β-Santalol

a) Preparation of (1S,2S,4R)-2-methyl-3-methylene-bicyclo[2.2.1]heptane:by enantioselective and exo-selective Diels-Alder reaction (according toMacMillan et coll., J. Am. Chem. Soc. 2000, 122, 4243 and PCT Int. Appl.2003002491)

A solution of(2S,5S)-(−)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone.HCl (0.1equiv) in MeOH/water (95:5) was treated with cyclopentadiene (3 molarequivalents) and crotonaldehyde (1 molar equivalent) for 24 hours atroom temperature. The 72:28 mixture of exo- and endo cycloadducts (both71% ee) (exo/endo with respect to CHO)) was reduced with LiAlH₄ (1 molarequivalent) in Et₂O at 25 to 30° C. to afford the corresponding exo- andendo-methyl-norbornenols in 30% yield (2 steps). These compounds couldbe separated by chiral SFC (supercritical fluid chromatography: OD-Hcolumn; co-solvent: MeOH: 5% (2 min), then +1% MeOH/min; flow: 2 ml/min;200 bar; 1^(st) peak exo major, 2^(nd) peak exo minor, 3^(rd) peak endomajor, 4^(th) peak endo minor). Enantiomeric enrichment of these knowncompounds can be effected by crystallization (Seebach et coll., J. Org.Chem. 1995, 60, 1788). The exo-enriched methyl-norbornenol washydrogenated (5% of 10% Pd on C; Et₂O, 99% yield). The exo-enrichedmethyl norbornanol was treated with Ac₂O (1.2 molar equivalents), NEt₃(2.0 molar equivalents), 4-dimethylaminopyridine (5 mol %), toluene at0° C. for 17 hours to afford the exo-enriched acetate in 74% yield. Thecompound so obtained was diluted in pentane (5%) and pyrolyzed at 610°C. through a 30 cm column filled with quartz pieces under a nitrogenflow to afford the optically active endo-enriched title compound in ca.80% yield.

-   Note: This compound (but exo-enriched) was also prepared by    Joachimsmann-Dufresne, Blanchard, Bull. Soc. Chim. France 1968, 385    by pyrolysis of the corresponding acetate (longer column, 510° C.).    In fact, Blanchard et coll. (Bull. Soc. Chim. France 1968, 385;    Bull. Soc. Chim. France 1972, 4770) prepared the title compound    (exo-enriched and racemic) from cyclopentadiene and crotonaldehyde    and the reduction/hydrogenation was performed in one step (H₂,    Raney-Ni, 90 bar, 110° C.).

The title compound thus obtained had a NMR characterisationcorresponding to the one of the compound obtained Example 1, method B,c).

a′) Preparation of(1S,2S,4R)-2-methyl-3-methylene-bicyclo[2.2.1]heptane: byenantioselective and exo-selective Diels-Alder reaction (according toHayashi et al., Angew. Chem. Int. Ed. 2008, 47, 6634)

A heterogeneous mixture of(S)-(+)-2-[bis-(3,5-trifluoromethylphenyl)trimethylsilyloxy-methyl]pyrrolidiniumperchlorate (5 mol %), water, freshly distilled crotonaldehyde (1 molarequivalent) and cyclopentadiene (3 molar equivalents) was stirred for 24hours at room temperature. The 72:28 mixture of exo- and endocycloadducts (95 respectively 76% ee) (exo/endo with respect to CHO))was reduced with NaBH₄ (1 molar equivalent) in MeOH at 25 to 30° C. toafford the corresponding exo- and endo- methyl-norbornenols in 49% yield(2 steps). The enantiomeric excesses of these compounds were determinedby chiral GC of the corresponding trifluoroacetates (Seebach et coll.,J. Org. Chem. 1995, 60, 1788) using a chiral capillary column(CP-Chirasil-DEX CB (25×0.25 mm, Chrompack). The methyl-norbornenolswere hydrogenated (5% of 10% Pd on C; Et₂O, 99% yield). Treatment of themethyl norbornanols with ClCOOEt (2 molar equivalents), pyridine (2.0molar equivalents) and toluene at 0° C. for 90 min and at roomtemperature for 30 min afforded the corresponding methyl carbonates in91% yield. The compound thus obtained was diluted in pentane (5%) andpyrolyzed at 415° C. through a 3 m column under a nitrogen flow toafford the optically active endo-enriched title compound in ca. 90%yield and 91% ee (chiral GC: first peak major (bad separation) togetherwith the exo-compound (endo/exo=72:28; exo: ca. 54% ee (second peakmajor)).

The title compound thus obtained had NMR characterisation correspondingto the one of the compound obtained Example 1, method B, c).

b) Preparation of(1R,4S)-1-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol: viaene-reaction

Me₂AlCl (1M in hexanes, 23.7 ml, 23.7 mmol) was added dropwise to asolution of trimethylsilyl-propynal (3.74 g; 80% pure, 23.7 mmol) and(1S,2S,4R)-2-endo-methyl-3-methylene-bicyclo[2.2.1]heptane (4.25; 65%pure; containing 25% of exo-isomer; 22.6 mmol) in dichloromethane (80ml) containing a few crystals of BHT at −78° C. under nitrogen. Themixture was stirred at −78° C. for 15 minutes and was poured intoaqueous HCl 5%. The product was extracted with ether. The combinedorganic layers were washed with water, conc. NaHCO₃ solution, brine,dried over Na₂SO₄ and filtered off to give a crude which wasbulb-to-bulb distilled (0.07 mbar/ oven temp. 120° C.) to afford(1R,4S)-1-(3-methyl-bicyclo[2.2.1]hept-2-en-2-yl)-4-trimethylsilanyl-but-3-yn-2-ol(4.84 g; 66% pure). It was dissolved in MeOH (50 ml) and treated withK₂CO₃ (3.23 G, 23.4 mmol) for 30 min at room temperature. Usualextraction (pentane/water) and bulb-to-bulb distillation afforded thetitle compound (3.09 g). Flash chromatography (SiO₂;cyclohexane/AcOEt=9:1) afforded pure title compound (2. 62 g; 66%). Thetitle compound thus obtained had NMR characterisation corresponding tothe one of the compound obtained Example 1, method A, f).

c) Preparation of(1S,2S,4R)-3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-alwith CuBF₄(CH₃CN)₄

It was proceeded as described above for the racemic compound (seeExample 2, a). Starting from(1R,4S)-1-(3-methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (2.02 g;11.5 mmol), 1.91 g (94%) of the title compound were obtained. Chiral GC:91% ee (first peak major). Low-temperature crystallization afforded thetitle compound with 97% ee (1.67 g).

[α]_(D) ²⁰: −267.4 (CHCl₃; c=1.06).

The title compound thus obtained had NMR characterisation correspondingto the one of the compound obtained Example 2, a).

d) Preparation of(1S,2R,4R)-3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-1-al

It was proceeded as described above for the racemic compound (seeExample 3, a), but MeOH/water (96:4) was used as the solvent.

Starting from(1S,2S,4R)-3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al (894 mg; 5.08 mmol), 769 mg (85%) of the title compound wereobtained. No separation by chiral GC.

[α]_(D) ²⁰: −112.3 (CHCl₃; c=0.86).

The title compound thus obtained had NMR characterisation correspondingto the one of the compound obtained Example 3, a).

e) Preparation of(1S,2R,4R)-2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-exo-2-yl)-pent-2-enal

It was proceeded as described above for the racemic compound (seeExample 3, B) i)) Starting from(1S,2R,4R)-3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-1-al,the title compound was obtained in 92% purity and 90% yield. Noseparation by chiral GC.

[α]_(D) ²⁰: −99.8 (CHCl₃; c=1.14).

The title compound thus obtained had NMR characterisation correspondingto the one of the compound obtained (see Example 3, B) i))

f) Preparation of and (−)-β-santalol

Application of the procedure for the racemic compound (via compounds IVand VII) (see Example 3, B) afforded (−)-β-santalol as a 94/6Z/E-mixture in 80% yield. Pure Z-(−)-β-santalol of 97% ee was obtainedby chromatography (SiO₂; cyclohexane/AcOEt=9:1).

[α]_(D) ²⁰: −104.3 (CHCl₃; c=0.76).

The title compound thus obtained had NMR characterisation correspondingto the one of the compound obtained Example 3, B).

1. A dienol compound of formula

in the form of any one of its stereoisomers or mixture thereof, whereinR represents a methyl or ethyl group; R¹ represents a hydrogen atom or amethyl or ethyl group; R⁴ represents a C₁-C₃ alkyl, alkenyl or acylgroup or a C₃-C₈ silyl group.
 2. The compound of claim 1, wherein R is amethyl group.
 3. The compound of claim 1, wherein R is an ethyl group.4. The compound of claim 1, wherein R¹ represents a hydrogen atom. 5.The compound of claim 1, wherein R¹ represents a methyl group.
 6. Thecompound of claim 1, wherein R¹ represents an ethyl group.
 7. Thecompound of claim 1, wherein R⁴ represents a C₁-C₃ alkyl group.
 8. Thecompound of claim 1, wherein R⁴ represents a C₁-C₃ alkenyl group.
 9. Thecompound of claim 1, wherein R⁴ represents a C₁-C₃ acyl group.
 10. Thecompound of claim 1, wherein R⁴ represents a C₃-C₈ silyl group.